Non-tumor suppressor roels of RASSF in RAS signaling

2021 Fiscal Year Final Research Report

• Project/Area Number: 19H03414
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 48040:Medical biochemistry-related
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Hata Yutaka 東京医科歯科大学, 大学院医歯学総合研究科, 教授 (80313237)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: シグナル伝達 / がん / 老化 / 神経

Outline of Final Research Achievements

RASSF proteins and the Hippo pathway that regulate transcriptional co-activators (TAZ and YAP1) are well-known tumor suppressors. In this sutdy. we obtained the following findings.
1) UNC119 binds to active RAS, enhances the interaction between RASSF6 and RAS, and subsequently activates RASSF6-MDM2-p53 axis. 2) DNA damage activates CDK9 to phosphorylate BAF53 and the phosphorylated BAF53 traps RASSF6 in the nucleus to promote BAF53-BAF60a-p53 complex. 3) the depletion of Rassf6 in mice augments NF-kB signaling. 4) CSE1L is involved in the nuclear incorporation of TAZ, so that CSE1L and TAZ co-operatively contribute to malignant transformation of cancers. 5) Heat shock inactivates LATS kinases via SRC and phosphatase, and eventually increases the amount of nuclear YAP1 to up-regulate NF-kB signaling, 6) PKC phosphorylates YAP1 and switches YAP1 from TEAD signaling to p73 signaling, so that PKC activators should be applicable to control cancers with the disorder of the Hippo pathway.

Free Research Field

医化学

Academic Significance and Societal Importance of the Research Achievements

多くのヒトがんにRASSFの機能欠損が認められ予後不良因子となっている。本研究の知見はRASSF6のみならず全てのRASSFに当てはまると予測される。本研究成果はRASSF機能欠損をもつヒトがんがなぜ治療に抵抗し悪性化するのかという問題の解明に貢献する。RASSFの欠損が炎症の増強を通じて、発がんの母地となり、がんの成育を促進するほか、代謝性疾患にも関係する可能性も明らかにした。CSE1Lががんを悪性化させる分子機構を明らかにした。YAP1が温熱応答に寄与するという予測外の事実を明らかにした。PKC活性化剤がYAP1に腫瘍抑制機能を付与し、がん治療薬として応用できる可能性を明らかにした。